Thymic adipogenesis and age-related thymic demise

胸腺脂肪生成和与年龄相关的胸腺死亡

• 批准号: 8960920
• 负责人: VISHWA DEEP DIXIT
• 金额: $ 41.63万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-01 至 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8960920
• 关键词: Ablation; Address; Adipocytes; Adipose tissue; Adult; Age; Aging; Aging-Related Process; Biological Models; Blood capillaries; Calories; Cell Lineage; Cell physiology; Cells; Clinical; Cues; Data; Deterioration; Development; Elderly; Emigrations; Employee Strikes; Endothelial Cells; Environment; Epithelial; Etiology; Event; Excision; Fatty Change; Fibroblasts; Functional disorder; Generations; Genes; Goals; Health; Hematopoietic; Homeostasis; Immune; Immune System Diseases; Immunity; Immunology; Infection; Label; Lead; Life; Lipids; Lymphopoiesis; Malignant Neoplasms; Membrane; Mesenchymal; Mus; Obesity; Peroxisome Proliferator-Activated Receptors; Process; Production; Proteins; Reporter; Research; Research Project Grants; Signal Transduction; Stromal Cells; T-Cell Development; T-Lymphocyte; Testing; Thymic epithelial cell; Thymus Gland; Time; Tracer; Transgenic Organisms; Vacuole; adipocyte differentiation; age related; base; capillary; cell type; chemokine; design; fibrogenesis; fighting; immune function; in vivo; lipid biosynthesis; middle age; novel; novel strategies; novel therapeutic intervention; prevent; progenitor; research study; thymocyte; transcription factor; venule

DESCRIPTION (provided by applicant): Diminished ability of thymus to produce naive T cells with progressive aging remains a fundamental and puzzling phenomenon for immunology and to-date, an intractable clinical condition that contributes to immune dysfunction in elderly. With advancing age, the thymus undergoes striking fibrotic and fatty changes that culminate in its transformation into adipose tissue. The lineage of ectopic adipocytes and the mechanism of development of thymic adipocytes during aging are not well understood. Using lineage-tracing, our research team has shown that FoxN1+ thymic epithelial cells (TECs), that are necessary for T cell development, can transition and give rise to thymic adipogenic precursors. Consistent with this new paradigm, our lates preliminary data provide further in vivo evidence that proadipogenic cells in aging thymus can originate from epithelial and endothelial lineages via a secondary mesenchymal precursor. Based on our novel findings, the central hypothesis of this proposal is that the transition of TECs and endothelial cells contribute towards the lineage of thymic adipocytes and leads to age-related thymic involution. The corollary is that blocking the fibrogenesis and pro- adipogenic signaling in TEC and endothelial lineage cells will protect against aging of thymus. Experiments in Aim 1 will test the hypothesis 1 that with advancing age transition of FoxN1+ cells into adipogenic precursors via epithelial-mesenchymal transition (EMT) process gives rise to ectopic thymic adipocytes and compromises the thymic stromal microenvironment. Aim 2 will test the hypothesis 2 that that endothelial-lineage cells serve as adipogenic progenitors and will reveal that blocking he ectopic adipocyte development in thymic perivascular space protect against thymic aging. The Aim 3 will test the hypothesis 3 that age-related fibrogenesis in thymus causes reduction in thymopoiesis and reveal that mechanisms that commit secondary mesenchymal cells into adipocytes participate in thymic dysfunction. The long-term goal of this research project is to understand the mechanisms that cause thymic adiposity and to develop new approaches to prevent or reverse the process of age-related thymic involution.

描述（由申请人提供）：胸腺产生具有渐进性衰老的幼稚T细胞的能力降低仍然是免疫学和迄今为止的基本和令人困惑的现象，这是一种棘手的临床疾病，导致老年人的免疫功能障碍。 随着年龄的增长，胸腺经历了惊人的纤维化和脂肪变化，导致其转化为脂肪组织。异位脂肪细胞的谱系和在衰老过程中胸腺脂肪细胞发育的机理尚不清楚。 使用谱系追踪，我们的研究团队表明，对于T细胞发育所必需的FOXN1+胸腺上皮细胞（TEC）可以过渡和 产生胸腺成脂的前体。 与这种新的范式一致，我们的LATE的初步数据提供了进一步的体内证据，表明乳房衰老的培养基细胞可以通过次级间质前体来源于上皮和内皮谱系。基于我们的新发现，该提议的中心假设是TEC和内皮细胞的过渡有助于胸腺脂肪细胞的谱系，并导致与年龄相关的胸腺涉及。 推论是阻塞TEC和内皮谱系细胞中的纤维化和辅助信号传导将防止胸腺衰老。 AIM 1中的实验将检验假设1，该假设1通过上皮 - 间质转变（EMT）过程将FOXN1+细胞的年龄过渡到脂肪生成前体，从而导致异位胸腺脂肪细胞，并损害胸膜基质微环境。 AIM 2将测试假设2，即内皮细胞是脂肪祖细胞，并将揭示胸腺周围的脂肪细胞发育阻断胸腺周围空间中的异位脂肪细胞的发育，可预防胸腺衰老。 AIM 3将检验假设3，胸腺中与年龄相关的纤维发生会导致胸腺胞菌的减少，并揭示将继发性间充质细胞促成脂肪细胞的机制参与胸膜功能障碍。 该研究项目的长期目标是了解引起胸腺肥胖的机制，并开发新的方法来预防或扭转与年龄相关的胸腺涉及过程。